Intravascular clotting is a major health problem in the US. Venous thromboembolism annually causes approximately 300,000 patients to be hospitalized and more than 50,000 deaths. About 948,000 people annually suffer an acute myocardial infarction and of these patients about 227,000 die. Coronary thrombosis is present in the majority of infarcts. Almost 400,000 individuals per year undergo a cerebral infarct and thrombophlebitis leading to pulmonary embolism causes many hospital deaths. In addition, thromboembolic disease contributes to postoperative deaths. Anticoagulant, antithrombotic and hemostatic drugs are thus important tools in the arsenal of the physician. The anticoagulant heparin is required for the heart-lung machine on which modern heart surgery is based. Medical treatment of thrombosis may be divided into three distinct areas: platelet suppression, anticoagulant, and fibrinolytic therapy. Major recent advances have been made in the synthesis of new drugs directed against platlets and in the use of plasminogen activators to activated the fibrinolytic system. In the area of anticoagulants, extensive research has been directed at an understanding of the mechanism of action of heparin and on the preparation of heparin analogues. Otherwise, essentially no new anticoagulant drugs have appeared in recent years. The coagulation pathway is now fairly well understood and most of the coagulation factors can be isolated and purified. Although extensive research has been directed at the design of inhibitors for thrombin, almost no systematic attempts have been made to design inhibitors for the other serine proteases involved in the blood coagulation pathway. The goals of this research are to design, synthesize, and test synthetic inhibitors for the serine proteases involved in the blood coagulation pathway. Both novel transition state inhibitors and mechanism-based (suicide) inhibitors will be evaluated with the purposes of obtaining compounds which will selectively inhibit only one or a few of the coagulation factors, and compounds which will be general inhibitors of most of the activated coagulation factors. This research should lead to a better understanding of the active site structures of the blood coagulation serine proteases; may produce clinically useful drugs; should stimulate medicinal chemists in pharmaceutical companies to synthesize more enzyme targeted antithrombotic agents; and will provide new tools for the in vivo and in vitro study of the role of the individual coagulation factors in blood coagulation.